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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Tissue selective effects of topoisomerase II inhibitors in vivo

ABSTRACT: One major class of anti-cancer drugs targets topoisomerase II to induce DNA double-strand breaks and cell death of fast growing cells. In vitro experiments showed that doxorubicin can induce histone eviction as well as DNA damage, while etoposide can only induce DNA damage. Here, we compare the transcription responses of different tissues to doxorubicin or etoposide treatment in vivo. Total RNA from respective tissues in FVB mice 1 day or 6 days post indicated drug treatment were extracted and compared to un-treated mice. Two mice were used for each treatment.

ORGANISM(S): Mus musculus

SUBMITTER: Baoxu Pang

PROVIDER: E-GEOD-33626 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin.

Pang Baoxu B Qiao Xiaohang X Janssen Lennert L Velds Arno A Groothuis Tom T Kerkhoven Ron R Nieuwland Marja M Ovaa Huib H Rottenberg Sven S van Tellingen Olaf O Janssen Jeroen J Huijgens Peter P Zwart Wilbert W Neefjes Jacques J

Nature communications 20130101

DNA topoisomerase II inhibitors are a major class of cancer chemotherapeutics, which are thought to eliminate cancer cells by inducing DNA double-strand breaks. Here we identify a novel activity for the anthracycline class of DNA topoisomerase II inhibitors: histone eviction from open chromosomal areas. We show that anthracyclines promote histone eviction irrespective of their ability to induce DNA double-strand breaks. The histone variant H2AX, which is a key component of the DNA damage respons ...[more]

PMID: 23715267

Similar Datasets

Distinct effects of topoisomerase II inhibitors on tumor cell lines (part 1)

Project description:One major class of anti-cancer drugs targets topoisomerase II to induce DNA double-strand breaks and cell death of fast growing cells. Here, we compare three members of this class - the antracyclines doxorubicin and aclarubicin, and a chemically unrelated compound, etoposide. Aclarubicin does not induce DNA breaks. We define a new activity for the antracyclines: unsupported histone eviction from ´open´ or loosely packed chromosomal areas reflecting exon and promoter regions. As a result, the epigenome and the transcriptome are strongly affected. Tissue culture cells were treated with doxorubicin, aclarubicin or etoposide for 2 hours. Then drugs were removed by extensive washing. cells were further cultured for indicated days before total RNA were extracted and compared to un-treated control.

2013-06-04 | E-GEOD-33624 | biostudies-arrayexpress

Distinct effects of topoisomerase II inhibitors on tumor cell lines (part 2)

2013-06-04 | E-GEOD-33625 | biostudies-arrayexpress

Tissue selective effects of topoisomerase II inhibitors in vivo

Project description:One major class of anti-cancer drugs targets topoisomerase II to induce DNA double-strand breaks and cell death of fast growing cells. In vitro experiments showed that doxorubicin can induce histone eviction as well as DNA damage, while etoposide can only induce DNA damage. Here, we compare the transcription responses of different tissues to doxorubicin or etoposide treatment in vivo.

2013-06-04 | GSE33626 | GEO

Topoisomerase II inhibitors and histone eviction

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-06-04 | E-GEOD-33634 | biostudies-arrayexpress

Genome-wide analysis of histone eviction by FAIRE-Seq

Project description:A major class of chemotherapeutics targets topoisomerase II for DNA double-strand breaks and cancer cell elimination. We compare four members of this class?the anthracyclines doxorubicin, daunorubicin and aclarubicin that does not induce DNA breaks?and a different compound, etoposide. We define a novel activity for anthracyclines: histone eviction from open chromosomal areas. Since histone variant H2AX is also evicted, DNA damage response is attenuated when compared to etoposide. Histone eviction also affects the epigenetic code and deregulates the transcriptome in cancer cells and organs such as the heart. Histone eviction by anthracyclines can drive apoptosis of topoisomerase-negative acute myeloid leukemia blasts in patients. Doxo- and daunorubicin combine the activities of two anti-cancer drugs: etoposide for DNA damage and aclarubicin for histone eviction. We define a novel mechanism of action of anti-cancer drugs doxo- and daunorubicin on chromatin biology with profound consequences on DNA damage responses, epigenetics, transcription, side effects and anti-cancer activities. Comparison of histone occupancy of cells or tissues treated with topoisomerase II inhibitors to un-treated ones by FAIRE-seq.

2013-06-04 | E-GEOD-33632 | biostudies-arrayexpress

Epigenetic changes due to histone eviction induced by anthracycline doxorubicin and aclarubicin

Project description:One major class of anti-cancer drugs targets topoisomerase II to induce DNA double-strand breaks and cell death of fast growing cells. Here, we compare three members of this class - the antracyclines doxorubicin and aclarubicin, and a chemically unrelated compound, etoposide. Aclarubicin does not induce DNA breaks. We define a new activity for the antracyclines: unsupported histone eviction from ´open´ or loosely packed chromosomal areas reflecting exon and promoter regions. Comparison of histone H3K4me3 of cells post topoisomerase II inhibitors treatment to un-treated ones by ChIP-seq. Comparison of phosphorylated histone H2AX of cells post topoisomerase II inhibitors doxorubicin and etoposide treatment to un-treated ones by ChIP-seq.

2013-06-04 | E-GEOD-33633 | biostudies-arrayexpress

Genome-wide analysis of histone eviction by FAIRE-Seq

2013-06-04 | GSE33632 | GEO

Epigenetic changes due to histone eviction induced by anthracycline doxorubicin and aclarubicin

2013-06-04 | GSE33633 | GEO

Detoxifying doxorubicin

Project description:The anthracycline doxorubicin is a highly effective anti-cancer drug associated with severe side effects, including secondary tumors and cardiotoxicity. Doxorubicin induces DNA damage through double-strand breaks (DSBs) and epigenetic or chromatin damage through histone eviction. We examined whether separation of these activities can help to detoxify doxorubicin, while maintaining its chemotherapeutic efficacy. We show that anthracycline variants harboring the histone eviction activity alone remain potent anti-cancer drugs, while greatly alleviating cardiotoxicity and secondary tumor formation. We thus demonstrate that treatment-limited side effects of doxorubicin can be synthesized away, yielding effective chemotherapeutics towards improved and prolonged treatment responses and higher patient quality of life.

2019-09-01 | GSE108179 | GEO

Distinct effects of topoisomerase II inhibitors on tumor cell lines (part 2)

2013-06-04 | GSE33625 | GEO

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